tbuckley/cabot-search huggingface dataset:
Mitochondrial pannexin1 controls cardiac sensitivity to ischaemia/reperfusion injury
Authors: Olga M Rusiecka, Filippo Molica, Morten S Nielsen, Axel Tollance, Sandrine Morel, Maud Frieden, Marc Chanson, Kerstin Boengler, Brenda R Kwak
Journal: Cardiovascular Research (2023)

No effective therapy is available in clinics to protect the heart from ischaemia/reperfusion (I/R) injury. Endothelial cells are activated after I/R, which may drive the inflammatory response by releasing ATP through pannexin1 (Panx1) channels. Here, we investigated the role of Panx1 in cardiac I/R.Panx1 was found in cardiac endothelial cells, neutrophils, and cardiomyocytes. After in vivo I/R, serum Troponin-I, and infarct size were less pronounced in Panx1-/- mice, but leukocyte infiltration in the infarct area was similar between Panx1-/- and wild-type mice. Serum Troponin-I and infarct size were not different between mice with neutrophil-specific deletion of Panx1 and Panx1fl/fl mice, suggesting that cardioprotection by Panx1 deletion rather involved cardiomyocytes than the inflammatory response. Physiological cardiac function in wild-type and Panx1-/- hearts was similar. The time to onset of contracture and time to maximal contracture were delayed in Panx1-/- hearts, suggesting reduced sensitivity of these hearts to ischaemic injury. Moreover, Panx1-/- hearts showed better recovery of left ventricle developed pressure, cardiac contractility, and relaxation after I/R. Ischaemic preconditioning failed to confer further protection in Panx1-/- hearts. Panx1 was found in subsarcolemmal mitochondria (SSM). SSM in WT or Panx1-/- hearts showed no differences in morphology. The function of the mitochondrial permeability transition pore and production of reactive oxygen species in SSM was not affected, but mitochondrial respiration was reduced in Panx1-/- SSM. Finally, Panx1-/- cardiomyocytes had a decreased mitochondrial membrane potential and an increased mitochondrial ATP content.Panx1-/- mice display decreased sensitivity to cardiac I/R injury, resulting in smaller infarcts and improved recovery of left ventricular function. This cardioprotective effect of Panx1 deletion seems to involve cardiac mitochondria rather than a reduced inflammatory response. Thus, Panx1 may represent a new target for controlling cardiac reperfusion damage.
Longitudinal Associations between Ambient Air Pollution and Angiogenic Biomarkers among Pregnant Women in the LIFECODES Study, 2006–2008
Authors: Yi Zheng, Thomas McElrath, David Cantonwine, Hui Hu
Journal: Environmental Health Perspectives (2023)

Background: Exposures to ambient air pollution during pregnancy have been linked to adverse pregnancy outcomes such as preeclampsia and fetal growth restriction. Although evidence has shown that women with preeclampsia have higher ratio of soluble fms-like tyrosine kinase 1 to placental growth factor (sFlt-1/PlGF ratio), the potential impact of air pollution on markers of placental growth and function has not been well studied. Objectives: We aimed to examine longitudinal associations between ambient air pollution exposure and angiogenic factors among pregnant women in LIFECODES, a prospective birth cohort and biorepository in Massachusetts in the United States. Methods: PlGF and sFlt-1 were measured among pregnant women using plasma samples collected around 10, 18, 26, and 35 wk’ gestation. Women’s exposures to ozone (O3), fine particulate matter with aerodynamic diameter ≤2.5μm (PM2.5), and nitrogen dioxide (NO2) within 1, 2, 4, and 8 wk prior to each plasma sample collection were estimated based on geocoded residential addresses, and mixed effect linear regression models were fitted to assess their associations with sFlt-1/PlGF ratio, sFlt-1 (ng/mL), and PlGF (pg/mL). Percent changes in outcomes associated with each interquartile range increase in exposures were reported, along with their 95% confidence intervals. Results: A total of 1,066 pregnant women were included. In the multipollutant models, significant associations were observed for increased sFlt-1/PlGF ratio (PM2.5 3–8 wk’ gestation, NO2: 35–39 wk’ gestation), elevated sFlt-1 (O3: 26–34 wk’ gestation, PM2.5: 3–8 wk’ gestation), decreased sFlt-1 (NO2: 4–8 wk’ gestation), and decreased PlGF (NO2: 34–39 wk’ gestation) after adjusting for sociodemographic status, smoking, drinking, body mass index, parity, history of chronic hypertension, and conception time. Discussion: Exposures to PM2.5 during early pregnancy and exposures to O3 and NO2 during late pregnancy were associated with increased sFlt-1/PlGF ratio, elevated sFlt-1 and with decreased PlGF, which may be a potential mechanism underlying ambient air pollution’s impacts on adverse pregnancy and birth outcomes. https://doi.org/10.1289/EHP11909
Penetrance and Prognosis of MYH7 Variant-Associated Cardiomyopathies
Authors: Mark Jansen, Remco de Brouwer, Fahima Hassanzada, Angela E. Schoemaker, Amand F. Schmidt, Maria D. Kooijman-Reumerman, Valentina Bracun, Martijn G. Slieker, Dennis Dooijes, Alexa M.C. Vermeer, Arthur A.M. Wilde, Ahmad S. Amin, Ronald H. Lekanne Deprez, Johanna C. Herkert, Imke Christiaans, Rudolf A. de Boer, Jan D.H. Jongbloed, J. Peter van Tintelen, Folkert W. Asselbergs, Annette F. Baas
Journal: JACC Heart Failure (2023)
Impact of BMI in Patients With Early Hormone Receptor–Positive Breast Cancer Receiving Endocrine Therapy With or Without Palbociclib in the PALLAS Trial
Authors: Georg Pfeiler, Dominik Hlauschek, Erica L. Mayer, Christine Deutschmann, Stephanie Kacerovsky-Strobl, Miguel Martin, Jane Lowe Meisel, Nicholas Zdenkowski, Sibylle Loibl, Marija Balic, Haeseong Park, Aleix Prat, Claudine Isaacs, Emilio Bajetta, Justin M. Balko, Merixtell Bellet-Ezquerra, Judith Bliss, Harold Burstein, Fatima Cardoso, Hannes Fohler, Theodoros Foukakis, Karen A. Gelmon, Matthew Goetz, Tufia C. Haddad, Hiroji Iwata, Jacek Jassem, Soo-Chin Lee, Barbro Linderholm, Maartje Los, Eleftherios P. Mamounas, Kathy D. Miller, Patrick G. Morris, Elisabetta Munzone, Einav Nili Gal-Yam, Alistair Ring, Lois Shepherd, Christian Singer, Christoph Thomssen, Ling-Ming Tseng, Pinuccia Valagussa, Eric P. Winer, Antonio C. Wolff, Gabriele Zoppoli, Jana Machacek-Link, Celine Schurmans, Xin Huang, Eric Gauthier, Christian Fesl, Amylou C. Dueck, Angela DeMichele, Michael Gnant, David Cameron, Sarra El-Abed, Hope S. Rugo, Guenther G. Steger, Tiffany Traina, Gustavo Werutsky, Norman Wolmark
Journal: Journal of Clinical Oncology (2023)

BMI affects breast cancer risk and prognosis. In contrast to cytotoxic chemotherapy, CDK4/6 inhibitors are given at a fixed dose, irrespective of BMI or weight. This preplanned analysis of the global randomized PALLAS trial investigates the impact of BMI on the side-effect profile, treatment adherence, and efficacy of palbociclib.
Genetic Evidence Strongly Supports Managing Weight and Blood Pressure in Addition to Glycemic Control in Preventing Vascular Complications in People With Type 2 Diabetes
Authors: Altayeb Ahmed, Hasnat Amin, Fotios Drenos, Naveed Sattar, Hanieh Yaghootkar
Journal: Diabetes Care (2023)

To investigate the causal association of type 2 diabetes and its components with risk of vascular complications independent of shared risk factors obesity and hypertension and to identify the main driver of this risk.We conducted Mendelian randomization (MR) using independent genetic variants previously associated with type 2 diabetes, fasting glucose, HbA1c, fasting insulin, BMI, and systolic blood pressure as instrumental variables. We obtained summary-level data for 18 vascular diseases (15 for type 2 diabetes) from FinnGen and publicly available genome-wide association studies as our outcomes. We conducted univariable and multivariable MR, in addition to sensitivity tests to detect and minimize pleiotropic effects.Univariable MR analysis showed that type 2 diabetes was associated with 9 of 15 outcomes; BMI and systolic blood pressure were associated with 13 and 15 of 18 vascular outcomes, respectively; and fasting insulin was associated with 4 and fasting glucose with 2. No robust association was found for HbA1c instruments. With adjustment for correlated traits in the multivariable test, BMI and systolic blood pressure, consistent causal effects were maintained, while five associations with type 2 diabetes (chronic kidney disease, ischemic heart disease, heart failure, subarachnoid hemorrhage, and intracerebral hemorrhage) were attenuated to null.Our findings add strong evidence to support the importance of BMI and systolic blood pressure in the development of vascular complications in people with type 2 diabetes. Such findings strongly support the need for better weight and blood pressure management in type 2 diabetes, independent of glucose lowering, to limit important complications.
Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study
Authors: Miquel Serra-Burriel, Adrià Juanola, Feliu Serra-Burriel, Maja Thiele, Isabel Graupera, Elisa Pose, Guillem Pera, Ivica Grgurevic, Llorenç Caballeria, Salvatore Piano, Laurens van Kleef, Mathias Reichert, Dominique Roulot, Juan M Pericàs, Jörn M Schattenberg, Emmanuel A Tsochatztis, Indra Neil Guha, Montserrat Garcia-Retortillo, Rosario Hernández, Jordi Hoyo, Matilde Fuentes, Carmen Expósito, Alba Martínez, Patricia Such, Anita Madir, Sönke Detlefsen, Marta Tonon, Andrea Martini, Ann T Ma, Judith Pich, Eva Bonfill, Marta Juan, Anna Soria, Marta Carol, Jordi Gratacós-Ginès, Rosa M Morillas, Pere Toran, J M Navarrete, Antoni Torrejón, Céline Fournier, Anne Llorca, Anita Arslanow, Harry J de Koning, Fernando Cucchietti, Michael Manns, Phillip N Newsome, Rubén Hernáez, Alina Allen, Paolo Angeli, Robert J de Knegt, Tom H Karlsen, Peter Galle, Vincent Wai-Sun Wong, Núria Fabrellas, Laurent Castera, Aleksander Krag, Frank Lammert, Patrick S Kamath, Pere Ginès, Marifé Alvarez, Peter Andersen, Paolo Angeli, Alba Ardèvol, Anita Arslanow, Luca Beggiato, Zahia Ben Abdesselam, Lucy Bennett, Bajiha Boutouria, Alessandra Brocca, M. Teresa Broquetas, Llorenç Caballeria, Valeria Calvino, Judith Camacho, Aura Capdevila, Marta Carol, Laurent Castera, Marta Cervera, Fernando Cucchietti, Anna de Fuentes, Rob de Knegt, Harry J de Koning, Sonke Detlefsen, Alba Diaz, José Diéguez Bande, Vanessa Esnault, Núria Fabrellas, Josep Lluis Falcó, Rosa Fernández, Céline Fournier, Matilde Fuentes, Peter Galle, Edgar García, Montserrat García-Retortillo, Esther Garrido, Pere Ginès, Rosa Gordillo Medina, Jordi Gratacós-Ginès, Isabel Graupera, Ivica Grgurevic, Indra Neil Guha, Eva Guix, Johanne Kragh Hansen, Rebecca Harris, Elena Hernández Boluda, Rosario Hernández-Ibañez, Jordi Hoyo, Arfan Ikram, Simone Incicco, Mads Israelsen, Marta Juan, Adrià Juanola, Ralf Kaiser, Patrick S Kamath, Tom H Karlsen, Maria Kjærgaard, Marko Korenjak, Aleksander Krag, Marcin Krawczyk, Philippe Laboulaye, Irina Lambert, Frank Lammert, Simon Langkjær Sørensen, Cristina Laserna-Jiménez, Sonia Lazaro Pi, Elsa Ledain, Vincent Levy, Katrine Prier Lindvig, Anne Llorca, Vanessa Londoño, Guirec Loyer, Ann T. Ma, Anita Madir, Michael Manns, Denise Marshall, M. Lluïsa Martí, Sara Martínez, Ricard Martínez Sala, Roser Masa-Font, Jane Møller Jensen, Rosa M Morillas, Laura Muñoz, Ruth Nadal, Laura Napoleone, JM Navarrete, Phillip N Newsome, Vibeke Nielsen, Martina Pérez, Juan Manuel Pericás-Pulido, Salvatore Piano, Judit Pich, Elisa Pose, Judit Presas Escobet, Matthias Reichert, Carlota Riba, Dominique Roulot, Ana Belén Rubio, Maria Sánchez-Morata, Jörn Schattenberg, Miquel Serra-Burriel, Feliu Serra-Burriel, Louise Skovborg Just, Milan Sonneveld, Anna Soria, Christiane Stern, Patricia Such, Maja Thiele, Marta Tonon, Pere Toran, Antoni Torrejón, Emmanuel A Tsochatzis, Laurens van Kleef, Paulien van Wijngaarden, Vanessa Velázquez, Ana Viu, Susanne Nicole Weber, Tracey Wildsmith
Journal: The Lancet (2023)
COVID-19 pandemic: a catalyst for accelerating global action on patient safety
Authors: Rebecca Grant, Daniel Benamouzig, Howard Catton, Vincent Chi-Chung Cheng, Neelam Dhingra, Ramanan Laxminarayan, Helena Legido-Quigley, Susanna Lorenzo Martinez, Kadar Marikar, Marc Mendelson, Pierre Parneix, Eli Perencevich, Hardeep Singh, Sarah Tschudin-Sutter, Shin Ushiro, Evelyn Wesangula, Céline Gardiol, Gerald Dziekan, Stephan Harbarth, Didier Pittet
Journal: The Lancet Infectious Diseases (2023)
A Randomized Controlled Clinical Trial of Nasal Immunization with Live Virulence Attenuated <i>Streptococcus pneumoniae</i> Strains Using Human Infection Challenge
Authors: Helen Hill, Elena Mitsi, Elissavet Nikolaou, Annie Blizard, Sherin Pojar, Ashleigh Howard, Angela Hyder-Wright, Jack Devin, Jesus Reiné, Ryan Robinson, Carla Solórzano, Simon P. Jochems, Tinashe Kenny-Nyazika, Elisa Ramos-Sevillano, Caroline M. Weight, Chris Myerscough, Daniella McLenaghan, Ben Morton, Emily Gibbons, Madlen Farrar, Victoria Randles, Hassan Burhan, Tao Chen, Adam D. Shandling, Joe J. Campo, Robert S. Heyderman, Stephen B. Gordon, Jeremy S. Brown, Andrea M. Collins, Daniela M. Ferreira
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated
Oxidized Low‐Density Lipoprotein (Ox‐LDL)‐Triggered Double‐Lock Probe for Spatiotemporal Lipoprotein Oxidation and Atherosclerotic Plaque Imaging
Authors: Xu Zhi, Yufen Sun, Fangjian Cai, Sisi Wang, Hu Gao, Fan Wu, Lei Zhang, Zhen Shen
Journal: Advanced Healthcare Materials (2023)

Low-density lipoprotein (LDL), especially oxidative modified LDL (Ox-LDL), is the key risk factor for plaque accumulation and the development of cardiovascular disease. Herein, a highly specific Ox-LDL-triggered fluorogenic-colorimetric probe Pro-P1 is developed for visualizing the oxidation and aggregation progress of lipoproteins and plaque. A series of green fluorescent protein chromophores with modified donor-acceptor structures, containing carbazole as an electron donor and various substituents including pyridine-vinyl (P1), phenol-vinyl (P2), N, N-dimethylaniline-vinyl (P3), and thiophene-vinyl (P4), have been synthesized and evaluated. Emission spectroscopy and theoretical calculations of P1-P4 indicate that P1 shows enhanced green fluorescence (λem = 560 nm) by inhibiting its twisted intramolecular charge transfer in the presence of Ox-LDL. This feature allows the selection of P1 as a sensitive probe to directly visualize ferroptosis and Cu2+ -mediated LDL oxidative aggregation via in situ formation of fluorophore-bound Ox-LDL in living cells. The red-emissive probe Pro-P1 (λem = 660 nm) is prepared via borate protection of P1, which can be cleaved into P1 under high expression of HOCl and Ox-LDL condition at the lesion site, resulting in enhanced green emission. The plaque area and size with clear boundaries can be delineated by colorimetric fluorescence imaging and fluorescence lifetime imaging with precise differentiation.
Histone methyltransferase KMT5C drives liver cancer progression and directs therapeutic response to PARP inhibitors
Authors: Yu Tong, Fan Wang, Songling Li, Wenyun Guo, Qianyu Li, Yifei Qian, Linfeng Li, Huifang Zhao, Yonglong Zhang, Wei-Qiang Gao, Yanfeng Liu
Journal: Hepatology (2023)

Background and Aims: Epigenetic plasticity is a major challenge in cancer-targeted therapy. However, the molecular basis governing this process has not yet been clearly defined. Despite the considerable success of poly(ADP-ribose) polymerase inhibitors (PARPi) in cancer therapy, the limited response to PARPi, especially in HCC, has been a bottleneck in its clinical implications. Herein, we investigated the molecular basis of the histone methyltransferase KMT5C (lysine methyltransferase 5C) that governs PARPi sensitivity and explored a potential therapeutic strategy for enhancing PARPi efficacy. Approach and Results: We identified KMT5C, a trimethyltransferase of H4K20, as a targetable epigenetic factor that promoted liver tumor growth in mouse de novo MYC/Trp53 −/− and xenograft liver tumor models. Notably, induction of KMT5C by environmental stress was crucial for DNA repair and HCC cell survival. Mechanistically, KMT5C interacted with the pivotal component of homologous recombination repair, RAD51, and promoted RAD51/RAD54 complex formation, which was essential for the activation of dsDNA breaks repair. This effect depended on the methyltransferase activity of KMT5C. We further demonstrated that the function of KMT5C in promoting HCC progression was dependent on RAD51. Importantly, either a pharmacological inhibitor (A196) or genetic inhibition of KMT5C sensitized liver cancer cells to PARPi. Conclusions: KMT5C played a vital role in promoting liver cancer progression by activating the DNA repair response. Our results revealed a novel therapeutic approach using the KMT5C inhibitor A196, concurrent with olaparib, as a potential HCC therapy.
FLT3 inhibitors as MRD-guided salvage treatment for molecular failure in FLT3 mutated AML
Authors: Jad Othman, Nicola Potter, Katya Mokretar, David Taussig, Anjum Khan, Pramila Krishnamurthy, Anne-Louise Latif, Paul Cahalin, James Aries, Mariam Amer, Edward Belsham, Eibhlin Conneally, Charles Craddock, Dominic Culligan, Mike Dennis, Caroline Duncan, Sylvie D. Freeman, Caroline Furness, Amanda Gilkes, Paraskevi Gkreka, Katherine Hodgson, Wendy Ingram, Manish Jain, Andrew King, Steven Knapper, Panagiotis Kottaridis, Mary Frances McMullin, Unmesh Mohite, Loretta Ngu, Jenny O’Nions, Katharine Patrick, Tom Rider, Wing Roberts, Marianne Tang Severinsen, Neill Storrar, Tom Taylor, Nigel H. Russell, Richard Dillon
Journal: Leukemia (2023)

Abstract Patients with FLT3 -mutated AML have a high relapse rate and suboptimal outcomes. Many have co-mutations suitable for measurable residual disease (MRD) monitoring by RT-qPCR and those destined to relapse can be identified by high or rising levels of MRD, called molecular failure. This provides a window for pre-emptive intervention, but there is little evidence to guide treatment. The use of FLT3 inhibitors (FLT3i) appears attractive but their use has not yet been evaluated. We identified 56 patients treated with FLT3i at molecular failure. The FLT3 mutation was an ITD in 52, TKD in 7 and both in 3. Over half of patients had previously received midostaurin. Molecular failure occurred at a median 9.2 months from diagnosis and was treated with gilteritinib ( n = 38), quizartinib ( n = 7) or sorafenib ( n = 11). 60% achieved a molecular response, with 45% reaching MRD negativity. Haematological toxicity was low, and 22 patients were bridged directly to allogeneic transplant with another 6 to donor lymphocyte infusion. 2-year overall survival was 80% (95%CI 69–93) and molecular event-free survival 56% (95%CI 44–72). High-sensitivity next-generation sequencing for FLT3 -ITD at molecular failure identified patients more likely to benefit. FLT3i monotherapy for molecular failure is a promising strategy which merits evaluation in prospective studies.
Prognostic significance of ETP phenotype and minimal residual disease in T-ALL: a Children’s Oncology Group study
Authors: Brent L. Wood, Meenakshi Devidas, Ryan J. Summers, Zhiguo Chen, Barbara Asselin, Karen R. Rabin, Patrick A. Zweidler-McKay, Naomi J. Winick, Michael J. Borowitz, William L. Carroll, Elizabeth A. Raetz, Mignon L. Loh, Stephen P. Hunger, Kimberly P. Dunsmore, David T. Teachey, Stuart S. Winter
Journal: Blood (2023)
Core mitochondrial genes are down-regulated during SARS-CoV-2 infection of rodent and human hosts
Authors: Joseph W. Guarnieri, Joseph M. Dybas, Hossein Fazelinia, Man S. Kim, Justin Frere, Yuanchao Zhang, Yentli Soto Albrecht, Deborah G. Murdock, Alessia Angelin, Larry N. Singh, Scott L. Weiss, Sonja M. Best, Marie T. Lott, Shiping Zhang, Henry Cope, Victoria Zaksas, Amanda Saravia-Butler, Cem Meydan, Jonathan Foox, Christopher Mozsary, Yaron Bram, Yared Kidane, Waldemar Priebe, Mark R. Emmett, Robert Meller, Sam Demharter, Valdemar Stentoft-Hansen, Marco Salvatore, Diego Galeano, Francisco J. Enguita, Peter Grabham, Nidia S. Trovao, Urminder Singh, Jeffrey Haltom, Mark T. Heise, Nathaniel J. Moorman, Victoria K. Baxter, Emily A. Madden, Sharon A. Taft-Benz, Elizabeth J. Anderson, Wes A. Sanders, Rebekah J. Dickmander, Stephen B. Baylin, Eve Syrkin Wurtele, Pedro M. Moraes-Vieira, Deanne Taylor, Christopher E. Mason, Jonathan C. Schisler, Robert E. Schwartz, Afshin Beheshti, Douglas C. Wallace
Journal: Science Translational Medicine (2023)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral proteins bind to host mitochondrial proteins, likely inhibiting oxidative phosphorylation (OXPHOS) and stimulating glycolysis. We analyzed mitochondrial gene expression in nasopharyngeal and autopsy tissues from patients with coronavirus disease 2019 (COVID-19). In nasopharyngeal samples with declining viral titers, the virus blocked the transcription of a subset of nuclear DNA (nDNA)–encoded mitochondrial OXPHOS genes, induced the expression of microRNA 2392, activated HIF-1α to induce glycolysis, and activated host immune defenses including the integrated stress response. In autopsy tissues from patients with COVID-19, SARS-CoV-2 was no longer present, and mitochondrial gene transcription had recovered in the lungs. However, nDNA mitochondrial gene expression remained suppressed in autopsy tissue from the heart and, to a lesser extent, kidney, and liver, whereas mitochondrial DNA transcription was induced and host-immune defense pathways were activated. During early SARS-CoV-2 infection of hamsters with peak lung viral load, mitochondrial gene expression in the lung was minimally perturbed but was down-regulated in the cerebellum and up-regulated in the striatum even though no SARS-CoV-2 was detected in the brain. During the mid-phase SARS-CoV-2 infection of mice, mitochondrial gene expression was starting to recover in mouse lungs. These data suggest that when the viral titer first peaks, there is a systemic host response followed by viral suppression of mitochondrial gene transcription and induction of glycolysis leading to the deployment of antiviral immune defenses. Even when the virus was cleared and lung mitochondrial function had recovered, mitochondrial function in the heart, kidney, liver, and lymph nodes remained impaired, potentially leading to severe COVID-19 pathology.